All Publications

  • Gorlin Syndrome: Assessing Genotype-Phenotype Correlations and Analysis of Early Clinical Characteristics as Risk Factors for Disease Severity. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Betancourt, N. J., Qian, M. F., Pickford, J. R., Bailey-Healy, I., Tang, J. Y., Teng, J. M. 2022: JCO2102385


    PURPOSE: Gorlin syndrome (GS) is a rare genetic disorder characterized by lifetime risk of basal cell carcinomas (BCCs), skeletal anomalies (SAs), and other extracutaneous neoplasms. There is great variation in disease severity, and a genotype-phenotype correlation has not been well established. Here, we investigate whether patients' clinical characteristics predict disease severity to inform clinical decision making.METHODS: Data of 248 patients with GS were collected between 2014 and 2021 from three institutions. Multivariable regression analyses were performed to investigate whether clinical characteristics predicted disease burden. Genotype-phenotype correlations were investigated in 40 patients.RESULTS: Patients with SAs had a mean increase of 120 lifetime BCCs (95% CI, 27.1 to 213) relative to patients without SAs. Those with ≥ 2 SAs had 2.45 increased odds (95% CI, 1.01 to 5.91) of advanced or metastatic BCCs. Moreover, the presence of multiple SAs was associated with 5.00 increased odds of having a keratocystic odontogenic tumor (95% CI, 2.22 to 11.3) and 2.79 increased odds of an ovarian fibroma (95% CI, 1.05 to 7.40). Genotype-phenotype analyses showed that missense/in-frame mutations were more likely to be hereditary compared with severe deleterious mutation types (100% v 27%; P = .004). In addition, heat map visualization illustrated that those with more deleterious variants, like large deletions, trended toward increased burden of SAs and BCCs per year.CONCLUSION: GS patients with SAs may be at greater risk for developing more numerous and severe BCCs and other neoplastic growths including keratocystic odontogenic tumors and ovarian fibromas. Current clinical guidelines suggest yearly follow-up in individuals with GS. Since SAs are usually recognized at the time of diagnosis, our results suggest that more vigilant lifetime multidisciplinary surveillance should be considered for these patients starting in childhood.

    View details for DOI 10.1200/JCO.21.02385

    View details for PubMedID 35333541

  • Direct observation of adaptive tracking on ecological time scales in Drosophila. Science (New York, N.Y.) Rudman, S. M., Greenblum, S. I., Rajpurohit, S., Betancourt, N. J., Hanna, J., Tilk, S., Yokoyama, T., Petrov, D. A., Schmidt, P. 2022; 375 (6586): eabj7484


    Direct observation of evolution in response to natural environmental change can resolve fundamental questions about adaptation, including its pace, temporal dynamics, and underlying phenotypic and genomic architecture. We tracked the evolution of fitness-associated phenotypes and allele frequencies genome-wide in 10 replicate field populations of Drosophila melanogaster over 10 generations from summer to late fall. Adaptation was evident over each sampling interval (one to four generations), with exceptionally rapid phenotypic adaptation and large allele frequency shifts at many independent loci. The direction and basis of the adaptive response shifted repeatedly over time, consistent with the action of strong and rapidly fluctuating selection. Overall, we found clear phenotypic and genomic evidence of adaptive tracking occurring contemporaneously with environmental change, thus demonstrating the temporally dynamic nature of adaptation.

    View details for DOI 10.1126/science.abj7484

    View details for PubMedID 35298245

  • Allelic polymorphism at foxo contributes to local adaptation in Drosophila melanogaster MOLECULAR ECOLOGY Betancourt, N. J., Rajpurohit, S., Durmaz, E., Fabian, D. K., Kapun, M., Flatt, T., Schmidt, P. 2021; 30 (12): 2817-2830


    The insulin/insulin-like growth factor signalling pathway has been hypothesized as a major determinant of life-history profiles that vary adaptively in natural populations. In Drosophila melanogaster, multiple components of this pathway vary predictably with latitude; this includes foxo, a conserved gene that regulates insulin signalling and has pleiotropic effects on a variety of fitness-associated traits. We hypothesized that allelic variation at foxo contributes to genetic variance for size-related traits that vary adaptively with latitude. We first examined patterns of variation among natural populations along a latitudinal transect in the eastern United States and show that thorax length, wing area, wing loading, and starvation tolerance exhibit significant latitudinal clines for both males and females but that development time does not vary predictably with latitude. We then generated recombinant outbred populations and show that naturally occurring allelic variation at foxo, which exhibits stronger clinality than expected, is associated with the same traits that vary with latitude in the natural populations. Our results suggest that allelic variation at foxo contributes to adaptive patterns of life-history variation in natural populations of this genetic model.

    View details for DOI 10.1111/mec.15939

    View details for Web of Science ID 000651388900001

    View details for PubMedID 33914989

    View details for PubMedCentralID PMC8693798

  • A clinal polymorphism in the insulin signaling transcription factor foxo contributes to life-history adaptation in Drosophila* EVOLUTION Durmaz, E., Rajpurohit, S., Betancourt, N., Fabian, D. K., Kapun, M., Schmidt, P., Flatt, T. 2019; 73 (9): 1774-1792


    A fundamental aim of adaptation genomics is to identify polymorphisms that underpin variation in fitness traits. In Drosophila melanogaster, latitudinal life-history clines exist on multiple continents and make an excellent system for dissecting the genetics of adaptation. We have previously identified numerous clinal single-nucleotide polymorphism in insulin/insulin-like growth factor signaling (IIS), a pathway known from mutant studies to affect life history. However, the effects of natural variants in this pathway remain poorly understood. Here we investigate how two clinal alternative alleles at foxo, a transcriptional effector of IIS, affect fitness components (viability, size, starvation resistance, fat content). We assessed this polymorphism from the North American cline by reconstituting outbred populations, fixed for either the low- or high-latitude allele, from inbred DGRP lines. Because diet and temperature modulate IIS, we phenotyped alleles across two temperatures (18°C, 25°C) and two diets differing in sugar source and content. Consistent with clinal expectations, the high-latitude allele conferred larger body size and reduced wing loading. Alleles also differed in starvation resistance and expression of insulin-like receptor, a transcriptional target of FOXO. Allelic reaction norms were mostly parallel, with few GxE interactions. Together, our results suggest that variation in IIS makes a major contribution to clinal life-history adaptation.

    View details for DOI 10.1111/evo.13759

    View details for Web of Science ID 000486096000006

    View details for PubMedID 31111462

    View details for PubMedCentralID PMC6771989